NBEAL2 is mutated in gray platelet syndrome and is required for biogenesis of platelet α-granules

Abstract

Gray Platelet Syndrome (GPS) is an autosomal recessive bleeding disorder with large platelets that lack α-granules. We found that mutations of NBEAL2 (neurobeachin-like 2), encoding a BEACH/ARM/WD40 domain protein, cause GPS. We demonstrated that human megakaryocytes and platelets express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets.

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

“…No BM reticulin staining results have been reported from earlier described XLTT families [3][4][5][6] or individuals with other inherited GATA1 mutations [8], who may therefore have been similarly affected. Evidence from the present study and others suggests that BM reticulin and/or collagen fibrosis accompanies human germline mutations in several genes that cause defective megakaryocyte maturation with thrombocytopenia and platelet a-granule deficiency (GATA1, NBEAL2, and GFI1B) [9,10]. Presentation with thrombocytopenia early in life or a life-long history of bleeding tendency should alert to the possibility of an inherited disorder.…”

“…Similarity with the autosomal inherited disorder gray platelet syndrome (GPS) has been observed concerning deficiency of platelet a-granules and splenomegaly [4,6,9]. But in contrast to GPS due to NBEAL2 or lately discovered GFI1B mutations, where myelofibrosis has been found characteristic [9,10], there have been no previous reports of bone marrow (BM) fibrosis in XLTT or other GATA1 exon 4 mutation disorders [6,11].…”

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

“…This was nicely illustrated in a recent study showing how GPS platelets are unable to deposit a-granule matrix proteins such as fibrinogen (Fg) and fibronectin or provide a a-granule-derived membrane pool for optimal platelet spreading and for consolidating platelet connections on microlesions of exposed subendothelium [9]. Notwithstanding the phenotypic variability, a large number of GPS families, all with autosomal recessive inheritance, genotyped with biallelic mutations in NBEAL2 [10][11][12][13]. Significantly, neurobeachin-like 2 (NBEAL2) is predicted to be scaffolding protein that intervenes in vesicle trafficking, it contains a Beige and ChediakHigashi (BEACH) domain also seen in lysosomal trafficking regulator (LYST) mutated in the Chediak-Higashi syndrome and associated with abnormal lysosomes and dense granules [14].…”

Disease gene identification strategies for exome sequencing

“…Yamaguchi et al 56 Glazov et al 57 Puente et al 58 Gunay-Aygun et al 59 Weedon et al 60 Homozygosity (Figure 3b Becker et al 31 Walsh et al 35 Wang et al 51a Bolze et al 61 Caliskan et al 62 Bilguvar et al 63 O'Sullivan et al 64 Barak et al 65 Hanson et al 66 Shaheen et al 67 Doi et el Only a single experiment is required.…”